Dasatinib belongs to a new class of targeted antitumoral drugs, the inhibitors of the tumoral growth; in particular it is an inhibitor of the tyrosine-kinase activity of BRC-ABL and further four oncogenic kinases which is mainly used in the treatment of chronic myelogenous leukemia (CML).
Chronic myelogenous leukemia (CML) is a myeloproliferative disease, caused by the anomalous growth of pluripotent hemopoietic stem cells, i.e. still able to proliferate and differentiate; these cells, as indicated by the adjective “myelogenous”, belong at first to the series leading to the formation of granulocytes, a type of white blood cells, but it may also be related to other cell series. The phases of the untreated disease are three: the initial or chronic phase, generally with a slow course, which length is from three to five years from the diagnosis; the accelerated phase which is observed in about the 2/3 of the patients with a length of two-fifteen months; the blastic phase, associated with an average survival of three-six months, which inevitably leads to death. In most of the patients it seems that CML is caused by the reciprocal translocation of DNA segments between the chromosomes 9 and 22, with formation of the so-called Philadelphia chromosome (Ph), corresponding to a chromosome 22 in which the fusion BCR-ABL gene was formed and code for a protein that makes the blastos “immortal”.
Dasatinib inhibits the activity of BCR-ABL through the competition with the ATP for the binding site on the tyrosine-kinase portion of the target protein of which the catalytic activity is inhibited, with the consequent block of the signal translation, so controlling the proliferation of the leukemia cells. Dasatinib is mainly used for the treatment of the patients who no longer respond to the treatment with imatinib.
Dasatinib is a compound of formula I
chemically known as N-(2-chloro-6-methylphenyl)-2-[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino]thiazol-5-carboxamide, described in WO 00/62778 and sold under the name Sprycel®.
Some processes for the preparation of dasatinib are known in the prior art. WO 00/62778 discloses a process for the synthesis of dasatinib as reported in the following scheme 1.

EP 1 711 481 discloses a process for the synthesis of dasatinib as reported in the following scheme 2.

US 2007/219370 discloses a process for the synthesis of dasatinib as reported in the following scheme 3.

U.S. Pat. No. 7,652,146 discloses a process for the synthesis of dasatinib as reported in the following scheme 4.

The processes known in the art involve reagents difficult to handle and with high environmental impact. Moreover, most of the processes described in the prior art include convergent or cyclization reactions which often lead to a decrease in the yields.
There is, therefore, the need to find a new process for the preparation of dasatinib which uses simple reactions with low environmental impact and which allows the use of cheap reagents which are easy to find on the market.
Therefore, an object of the present invention is a process for the preparation of dasatinib which uses cheap and with low environmental impact reagents easy to find on the market.
The process for the synthesis of dasatinib, which is an object of the present invention, comprises:                a) the reaction of the compound of formula X        
                 with the compound of formula IX        
                 in an aprotic polar solvent and in the presence of a base, to give the compound of formula VIII        
                b) the protection reaction of the compound of formula VIII to give a compound of formula VII        
                 wherein PG is an amine protecting group;        c) the hydrolysis reaction of a compound of formula VII to give a compound of formula VI        
                d) the reaction of a compound of formula VI with the compound of formula V        
                 to give a compound of formula IV        
                e) the coupling reaction of a compound of formula IV with the compound of formula III        
                 in the presence of a base in a suitable solvent to give a compound of formula II        
                 and the simultaneous deprotection of said compound of formula II to give dasatinib of formula I or a salt thereof.        
In step a) of the process of the present invention, the aprotic polar solvent is preferably selected from among N-methylpyrrolidone, dimethylacetamide, dimethylformamide, tetrahydrofuran, methyl-tetrahydrofuran or mixtures thereof. Dimethylacetamide is preferably used.
In step a) of the process of the present invention the base is preferably selected from among sodium hydride, potassium hydride, and lithium hydride. Sodium hydride is preferably used.
In step b) of the process of the present invention, PG is preferably selected from among a ter-butoxycarbonyl (BOC), methoxymethyl (MOM), trifluoroacetyl, acetyl, and triphenylmethyl (trityl). Ter-butoxycarbonyl is more preferably used.
The introduction of the protecting group is carried out through the reaction with a suitable reagent such as for example diter-butyl dicarbonate, triphenylmethyl chloride, acetyl chloride, acetic anhydride, etc.; in the presence of a base in a suitable polar or apolar solvent or mixtures thereof. The base used is preferably selected from among N,N-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). Still more preferably, the base is N,N-dimethylaminopyridine (DMAP). The polar solvent is preferably selected from among tetrahydrofuran, methyl-tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or mixtures thereof, while the apolar solvent is preferably selected from among toluene, xylene or mixtures thereof. Tetrahydrofuran is the solvent preferably used.
In step c) of the process of the present invention the hydrolysis is carried out in the presence of a base, preferably an inorganic base selected from among lithium hydroxide, sodium hydroxide and sodium carbonate, still more preferably lithium hydroxide, in a polar aprotic solvent preferably selected from among tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, and dimethylacetamide. Still more preferably the polar aprotic solvent is tetrahydrofuran.
Step d) of the process of the present invention is carried out through an intermediate of formula VIa
wherein PG is an amine protecting group and has the above reported meanings; obtained by reacting a compound of formula VI with an organic tertiary amine, preferably selected from among triethylamine (TEA), pyridine, N,N-dimethylaminopyridine (DMAP), and N,N-diisopropylethylamine (DIPEA), still more preferably triethylamine, followed by the reaction with a chlorinating agent preferably selected from among oxalylchloride and tionylchloride, in an apolar solvent preferably selected from among methylene chloride, xylene or mixtures thereof. Tionyl chloride in methylene chloride is still more preferably used. The compound VIa is not isolated but is directly used in the subsequent step e).
The reaction between the compound of formula VIa and the compound of formula V is carried out in an apolar solvent preferably selected from among methylene chloride, xylene or mixtures thereof; with methylene chloride still more preferably used.
Step e) of the process of the present invention is carried out in the presence of a base preferably selected from among sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Still more preferably, the base is sodium carbonate. The solvent is an aprotic polar solvent preferably selected from among tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, and dimethylacetamide, and still more preferably is dimethylsulfoxide.
Under these conditions also the simultaneous deprotection of the compound of formula II, which is then not isolated in the process of the present invention, is obtained.
The compounds of formula VII, VI, VIa, IV and II are new intermediates useful for the synthesis of dasatinib and therefore are a further object of the present invention.
In a preferred embodiment, the process for the synthesis of dasatinib comprises:                a) the reaction of the compound of formula X        
                 with the compound of formula IX        
                 in an aprotic polar solvent and in the presence of a base, to give the compound of formula VIII        
                b) the protecting reaction of the compound of formula VIII to give the compound of formula VII        
                 wherein PG is ter-butoxycarbonyl;        c) the hydrolysis reaction of the compound of formula VII to give the compound of formula VI        
                 wherein PG is ter-butoxycarbonyl;        d) the reaction of the compound of formula VI with the compound of formula V        
                 to give the compound of formula IV        
                 wherein PG is ter-butoxycarbonyl;        e) the coupling reaction of the compound of formula IV with the compound of formula III        
                 in the presence of a base in a suitable solvent to give the compound of formula II        
                 wherein PG is ter-butoxycarbonyl;        and the simultaneous deprotection of said compound of formula II to give dasatinib of formula I or a salt thereof.        
In step a) of the process of the present invention, the aprotic polar solvent is preferably selected from among N-methylpyrrolidone, dimethylacetamide, dimethylformamide, tetrahydrofuran, methyl-tetrahydrofuran or mixtures thereof. Dimethylacetamide is preferably used.
In step a) of the process of the present invention the base is preferably selected from among sodium hydride, potassium hydride, and lithium hydride. Sodium hydride is preferably used.
The introduction of the protecting group ter-butoxycarbonyl is carried out through the reaction with a suitable reagent such as for example diter-butyl dicarbonate in the presence of a base in a suitable polar or apolar solvent or mixtures thereof. The base used is preferably selected from among N,N-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). Still more preferably, the base is N,N-dimethylaminopyridine (DMAP). The polar solvent is preferably selected from among tetrahydrofuran, methyl-tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or mixtures thereof, while the apolar solvent is preferably selected from among toluene, xylene or mixtures thereof. Tetrahydrofuran is the solvent preferably used.
In step c) of the process of the present invention, the hydrolysis is carried out in the presence of a base, preferably an inorganic base selected from among lithium hydroxide, sodium hydroxide and sodium carbonate, still more preferably lithium hydroxide, in a polar aprotic solvent preferably selected from among tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, and dimethylacetamide. Still more preferably, the polar aprotic solvent is tetrahydrofuran.
Step d) of the process of the present invention is carried out through an intermediate of formula VIa
wherein PG is ter-butoxycarbonyl;obtained by reacting a compound of formula VI with an organic tertiary amine, preferably selected from among triethylamine (TEA), pyridine, N,N-dimethylaminopyridine (DMAP), and N,N-diisopropylethylamine (DIPEA), still more preferably triethylamine, followed by the reaction with a chlorinating agent preferably selected from among oxalylchloride and tionylchloride, in an apolar solvent preferably selected from among methylene chloride, xylene or mixtures thereof. Tionyl chloride in methylene chloride is still more preferably used. The compound VIa is not isolated but is directly used in the subsequent step e).
The reaction between the compound of formula VIa and the compound of formula V is carried out in an apolar solvent preferably selected from among methylene chloride, xylene or mixtures thereof. Methylene chloride is still more preferably used.
Step e) of the process of the present invention is carried out in the presence of a base preferably selected from among sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Still more preferably, the base is sodium carbonate. The solvent is an aprotic polar solvent preferably selected from among tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, and dimethylacetamide. Still more preferably, the aprotic polar solvent is dimethylsulfoxide.
Under these conditions also the simultaneous deprotection of the compound of formula II, which is then not isolated in the process of the present invention, is obtained.
All the terms used in the present description, unless otherwise indicated, are to be understood in their common meaning as known in the art. Other more specific precise definitions for certain terms, as used in the present description, are highlighted herein after and constantly applied in the whole description and claims, unless a different definition provides specifically a broader meaning.
The term “polar solvent” refers to a solvent which is a proton donor, such as water; an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol; or a polarized solvent such as, for example, esters, for example ethylacetate, butyl acetate; nitriles, for example, acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example, acetone, methylbutylketone and the like.
Further information about non polar or polar, protic or aprotic solvents can be found in organic chemistry books or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. II, in “Techniques of Chemistry Series”, John Wiley & Sons, NY, 1986. Such solvents are known to the person skilled in the art and it is moreover clear to the person skilled in the art that different solvents or mixtures thereof can be selected and preferred, depending on the specific compounds and on the reaction conditions, being their choice influenced, for example, by solubility and reagent reactivity, by preferred temperature ranges.
Although the present invention has been described in its characterizing features, the equivalents and modifications obvious to the skilled in the art are included in the present invention.
The present invention will be now illustrated through some examples without limiting the scope of the invention.